Chronic obstructive pulmonary disease (COPD), a disease characterized by airflow obstruction due to chronic bronchitis and emphysema, affects more than 16 million Americans and is currently the fourth most common cause of death. COPD is continuing to increase in both prevalence and mortality, with the cost of care estimated to be approximately $24 billion/yr. It is generally accepted that COPD is a multifactorial disease the pathophysiology of which is associated with in influx of neutrophils and other phagocytic cells to the lungs, and the subsequent release of an array of proteases, leading to an imbalance between the levels of the proteases and their endogenous protein inhibitors. This imbalance results in poor regulation of the activity of these enzymes, which then degrade the major components of the extracellular matrix, ultimately leading to the onset of disease. It is hypothesized herein that agents capable of regulating selectively the activity of the renegade enzymes, thereby re-establishing a protease-antiprotease balance, are of value as probes for delineating the precise role of a particular protease in COPD, and as potential therapeutic agents. Thus, the specific aims of the proposed research are (a) structure-based design and synthesis of selective inhibitors of various proteases implicated in COPD based on an array of heterocyclic scaffolds. This aim includes the formulation and validation of a general strategy related to the design of selective inhibitors of (chymo)trypsin-like mammalian, viral and bacterial proteases; (b) structure-based design and synthesis of two novel and general classes of inhibitors of serine, cysteine and metallo-proteases; (c) design of a novel class of mechanism-based inhibitors of serine proteases that are postulated to inactivate a target enzyme via an unprecedented enzyme-induced 3-aza Grob fragmentation process and, (d) biochemical and structural studies aimed at determining the inhibitory activity, enzyme selectivity and mechanism of action of the inhibitors.